Antimicrobial compositions

ABSTRACT

Antimicrobial compositions are provided that include a hydroalcoholic solvent system comprising a lower C 2 -C 5  alcohol and water; a cationic antimicrobial agent such as chlorhexidine gluconate; a fatty component containing at least one free hydroxyl group, such as a C 12 -C 21  fatty alcohol, a C 12 -C 21  fatty ester, a C 12 -C 21  fatty ether, a C 12 -C 21  fatty amide, and combinations thereof; and optionally an emollient ester such as diesters of bibasic acids and triesters of citric acid. The compositions described herein display improved antimicrobial efficacy and improved cosmetic elegance.

BACKGROUND

It is a standard practice in the industrialized world to disinfect theskin prior to any invasive procedure such as surgery, catheterization,or needle puncture to reduce the risk of infection. Currently,chlorhexidine compositions are an agent of choice for disinfectinghands, skin, surgical sites, catheter sites, and oral cavities.Chlorhexidine and its salts are well-known antimicrobials with excellentefficacy that are safe to use. Chlorhexidine and its salts also showpersistent antimicrobial activity on the skin often for more than 24hours.

Two hydroalcoholic compositions containing chlorhexidine are currentlyavailable. AVAGARD surgical hand prep is a hydroalcoholic compositioncontaining 1% chlorhexidine gluconate in 61% ethanol available from 3MCompany. CHLOROPREP surgical prep is a composition containing 2% w/vchlorhexidine gluconate (CHG), 70% v/v isopropanol, and water availablefrom Mediflex, Inc.

Products that contain chlorhexidine or its derivatives suffer fromseveral disadvantages. Chlorhexidine is a cationic bisguanide, which canbe readily deactivated by salts (chlorides, carbonates, and the like),nonionic surfactants, anionic surfactants, and anionic compounds such asorganic acids or salts of organic acids. Many soaps and skin creamscontain these agents and readily deactivate chlorhexidine and its salts.Chlorhexidine compositions can also be irritating to skin and mucousmembranes. Products that contain greater than 2% CHG can causesignificant irritation, particularly after repeated use.

Surgical preps containing chlorhexidine and/or other antimicrobials canundermine the adhesion of medical tapes, dressings, and surgical drapes,particularly under wet skin conditions. Chlorhexidine salts inparticular exacerbate this problem because they are hydrophilic and siton the surface of the skin after topical application. Under wetconditions, such as in surgery when large amounts of body fluids orsaline are present, the chlorhexidine salts can cause the loss ofadhesion of surgical drapes and dressings. This adhesion loss is oftencalled “drape lift” and is highly undesirable because it can interruptthe sterile field, which increases the probability of a surgical siteinfection.

There is a clear need for chlorhexidine compositions which have lowirritation, cosmetic acceptability, excellent efficacy, and improved wetadhesion for use in surgical and catheter sites.

SUMMARY OF THE INVENTION

The present invention provides compositions useful as products for skindisinfection such as skin antiseptics, preoperative surgical preps, handsanitizers, catheter and i.v. skin preps, and waterless hand scrubs. Thepreferred formulations of the present invention, in general, have adesirable cosmetic feel after both single and multiple applications.Additionally, preferred formulations maintain or improve adhesion ofmedical articles to skin, particularly in the presence of moisture. Whenused as a preoperative surgical prep or antiseptic, the compositionsdescribed herein achieve improved antimicrobial efficacy.

In one aspect, an antimicrobial composition is provided, comprising:

-   -   a) a C₂-C₅ lower alcohol present in an amount of at least 35        wt-%;    -   b) a fatty component containing one or more free hydroxyl groups        selected from the group consisting of C₁₂-C₂₁ fatty alcohols,        C₁₂-C₂₁ fatty ethers, C₁₂-C₂₁ fatty amides, and combinations of        all of the foregoing; and    -   c) a cationic antimicrobial agent;

wherein the antimicrobial composition is free of surfactants with an HLBgreater than 6; and wherein the antimicrobial composition is essentiallyfree of hydrophilic polymers.

In another aspect, an antimicrobial composition is provided, comprising:

-   -   a) a C₂-C₅ lower alcohol present in an amount of at least 35        wt-%;    -   b) a fatty component containing one or more free hydroxyl groups        selected from the group consisting of C₁₂-C₂₁ fatty alcohols,        C₁₂-C₂₁ fatty esters, C₁₂-C₂₁ fatty ethers, C₁₂-C₂₁ fatty        amides, and combinations of all of the foregoing;    -   c) a cationic antimicrobial agent; and    -   d) an emollient ester selected from the group consisting of        diesters of bibasic acids, triesters of citric acid, diesters of        diols, triesters of triols, and combinations thereof.

In a further aspect, an antimicrobial composition is provided,comprising:

-   -   a) a C₂-C₅ lower alcohol present in an amount of at least 35        wt-%;    -   b) a C₁₂-C₂₁ fatty ether with at least one hydroxyl group; and    -   c) a cationic antimicrobial agent;        wherein the antimicrobial composition is essentially free of        surfactants.

In a further aspect, an antimicrobial composition is provided,comprising:

-   -   a) a C₂-C₅ lower alcohol present in an amount of at least 35        wt-%;    -   b) a C₁₂-C₂₁ fatty amide with at least one hydroxyl group; and    -   c) a cationic antimicrobial agent;        wherein the fatty amide is soluble in the composition.

In another aspect, an antimicrobial composition is provided, comprising:

-   -   a) a C₂-C₅ lower alcohol present in an amount of at least 35        wt-%;    -   b) a fatty component containing one or more free hydroxyl groups        selected from the group consisting of C₁₂-C₂₁ fatty alcohols,        and C₁₂-C₂₁ fatty esters;    -   c) a cationic antimicrobial agent; and    -   d) an emollient ester selected from the group consisting of        diesters of bibasic acids, diesters of diols, triesters of        citric acid, trimesters of triols and combinations thereof;        wherein the emollient ester is present in an amount greater than        1 wt-% based on the total weight of the composition.

In another aspect, an antimicrobial composition is provided, comprising:

-   -   a) a C₂-C₅ lower alcohol present in an amount of at least 35        wt-%;    -   b) a C₁₂-C₂₁ fatty esters containing one or more free hydroxyl        groups in an amount greater than 1 wt-% based on the total        weight of the composition; and    -   c) a cationic antimicrobial agent;        wherein the antimicrobial composition is free of silicones; and        wherein the antimicrobial composition is essentially free of        surfactants.

In a further aspect, a nonvolatile antimicrobial composition isprovided, comprising

-   -   (a) a fatty component containing one or more free hydroxyl        groups selected from the group consisting of C₁₂-C₂₁ fatty        alcohols, C₁₂-C₂₁ fatty esters, C₁₂-C₂₁ fatty ethers, C₁₂-C₂₁        fatty amides, and combinations of all of the foregoing; and    -   (b) a cationic antimicrobial agent;    -   (c) an optional emollient ester selected from the group        consisting of diesters of bibasic acids, triesters of citric        acid, diesters of diols, triesters of triols, and combinations        thereof;        wherein the nonvolatile antimicrobial composition is essentially        free of surfactants.

Methods are also provided with the compositions above. In one aspect, amethod of improving the wet adhesion of medical adhesive article isprovided, comprising applying a composition comprising:

-   -   a) a C₂-C₅ lower alcohol present in an amount of at least 35        wt-%;    -   b) a fatty component containing one or more free hydroxyl groups        selected from the group consisting of C₁₂-C₂₁ fatty alcohols,        C₁₂-C₂₁ fatty esters, C₁₂-C₂₁ fatty ethers, C₁₂-C₂₁ fatty        amides, and combinations of all of the foregoing;    -   c) a cationic antimicrobial agent; and        applying a medical adhesive article over the composition;        wherein the medical adhesive article has improved adhesion to        skin as measured by the Wet Skin Adhesion test.

In a further aspect, a method of preventing or treating a skin conditionof a mammal, the method comprising the step of applying theantimicrobial compositions of any of the compositions above to skin.

In another aspect, a method of preventing surgical site or catheter siteinfections is provided, the method comprising the step of applying theantimicrobial compositions of any of the compositions above prior tosurgery or catheterization.

DEFINITIONS

“Ambient temperature” as used herein refers to the temperature rangebetween about 21° and 25° C.

“Emollient” as used herein refers to materials which are capable ofmaintaining or improving the moisture level, compliance, or appearanceof the skin when used repeatedly. Emollients often act to increase themoisture content of the stratum corneum. Emollients are generallyseparated into two broad classes based on their function. The firstclass of emollients function by forming an occlusive barrier, whichreduces water evaporation from the stratum corneum. The first class ofemollients is further subdivided into compounds, which are waxes at roomtemperature and compounds which are liquid or oils. The second class ofemollients penetrate into the stratum corneum and physically bind waterto prevent evaporation. The second class of emollients includes thosethat are water soluble and are often referred to as humectants. For thepurposes of this invention, the emollient esters are considered separateand distinct from any other emollients which may be used in thecompositions described herein, even though the emollient esters may alsofunction as occlusive emollients and aid in maintaining or improving theskin condition.

“Polymer” as used herein refers to a natural or synthetic moleculehaving repetitive units and a number average molecular weight of atleast 10,000.

“Lotion” means liquid or cream, free of any propellant.

“Solvent system” or “hydroalcoholic solvent system” as used herein referto the combination of the lower (C₂-C₅) alcohol and water in thecompositions described herein.

“Solvent” as used herein refers to any organic compound used to dissolveor disperse another compound. Common solvents include lower alcohols,acetone, methyl ethyl ketone, volatile ethers, water and toluene.

“Surfactant” as used herein is synonymous with “emulsifier,” and meansan amphiphile (a molecule possessing both polar and nonpolar regionswhich are covalently bound) capable of reducing the surface tension ofwater and/or the interfacial tension between water and an immiscibleliquid.

“Fatty” as used herein refers to a hydrocarbon chain length of 8 or morecarbon atoms (odd or even number), unless otherwise specified.

“Cidatrope” as used herein is a term for a hydrophobic component in thecomposition that enhances the effectiveness of the antimicrobialcomposition such that when the composition less the antimicrobial agentand the composition less the cidatrope component are used separately,they do not provide the same level of antimicrobial activity as thecomposition as a whole. For example, a cidatrope component in theabsence of the antimicrobial agent may not provide any appreciableantimicrobial activity. The enhancing effect can be with respect to thelevel of kill, the speed of kill, and/or the spectrum of microorganismskilled, and may not be seen for all microorganisms. The cidatropecomponent may act synergistically such that when combined with theremainder of the composition, the composition as a whole displays anactivity that is greater than the sum of the activity of the compositionless the cidatrope component and the composition less the antimicrobialagent. The cidatrope preferably is a wax at ambient conditions with amelt temperature greater than 23° C. When more than one cidatrope ispresent in the antimicrobial composition, at least one cidatrope has amelt temperature greater than 23° C. Both the fatty component and theemollient esters are cidatropes in the compositions described herein.

“Hydrophobic” or “water insoluble” refers to a material that will notsignificantly dissolve in water at 23° C. Solubility can be determinedby thoroughly mixing the compound with water at the appropriateconcentration at 23° C. for at least 24 hours (or at elevatedtemperature if that is necessary to dissolve the compound), allowingthis to sit at 23-25° C. for 24 hours, and observing the sample. In aglass jar with a 4-cm path length the sample should have evidence of asecond phase, which can be liquid or solid and may be separated on thetop, bottom, or distributed throughout the sample. For crystallinecompounds care should be taken to avoid producing a supersaturatedsolution. The components should be mixed and observed. Cloudiness orpresence of a visible precipitate or separate phase indicates that thesolubility limit has been exceeded. Typically, when placed in 1×1 cmcell the sample has less than 70% transmission measured in a suitablespectrophotometer at a wavelength of 655 nm. For solubilitydeterminations less than that which can be observed with the naked eyethe solubility is determined using radiolabeled compounds as describedunder “Conventional Solubility Estimations in Solubility of Long-ChainFatty Acids in Phosphate Buffer at pH 7.4,” Henrik Vorum, et al. inBiochimica et. Biophysica Acta, 1126, 135-142 (1992).

“Hydrophilic” or “water soluble” refers to a material that will dissolveor disperse in water (or other aqueous solution as specified) at atemperature of 23° C. in an amount of at least 7% by weight, preferablyat least 10% by weight, more preferably at least 20% by weight, evenmore preferably at least 25% by weight, even more preferably at least30% by weight, and most preferably at least 40% by weight, based on thetotal weight of the hydrophilic material and the water. The component isconsidered dissolved if after thoroughly mixing the compound with waterat 60° C. for at least 4 hours and allowing this to cool to 23-25° C.for 24 hours, and mixing the composition thoroughly it appears uniformclear solution without visible cloudiness, phase separation, orprecipitate in ajar having a path length of 4 cm. Typically, when placedin 1×1 cm cell, the sample exhibits greater than 70% transmissionmeasured in a suitable spectrophotometer at a wavelength of 655 nm.Water dispersible hydrophilic materials disperse in water to formuniform cloudy dispersions after vigorous shaking of a 5% by weightmixture of the hydrophilic component in water.

“Nonvolatile” means that the component does not evaporate readily atambient conditions, such that a 20 gm sample in a 4 cm² dish does notlose more than 2% of its weight, e.g., within 60 minutes upon exposureto ambient conditions. Examples of nonvolatile components of thecompositions described herein include glycerin, chlorhexide and itssalts, and fatty components with a chain length greater than 10 carbons.

“Essentially free” means less than 1% by weight, more preferably lessthan 0.5% by weight, and even more preferably less than 0.1% by weight,of a component based on the total weight of the composition.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compositions provided herein are hydroalcoholic formulations thatprovide rapid and persistent antimicrobial activity. The compositionsinclude a hydroalcoholic solvent system comprising a lower C₂-C₅ alcoholand water, and a cationic antimicrobial agent such as chlorhexidinegluconate. The compositions also include a fatty component containing atleast one free hydroxyl group, such as a C₁₂-C₂₁ fatty alcohol, aC₁₂-C₂₁ fatty ester, a C₁₂-C₂₁ fatty ether, a C₁₂-C₂₁ fatty amide, andcombinations thereof. In most embodiments, the compositions also includea hydrophobic emollient ester such as diesters of bibasic acids andtriesters of citric acid. The compositions of this invention are usefulas preoperative surgical preps, hand antiseptics, dental antiseptics andvarnishes, antimicrobial swaps, and wipes for skin disinfection. Thecompositions are particularly useful for preventing surgical site andcatheter site infections when used as an antiseptic on the skin.

The compositions described herein display improved antimicrobialefficacy and improved cosmetic elegance. Improved antimicrobial efficacymeans a composition that exhibits any one or a combination of thefollowing: (i) the composition maintains antimicrobial activity in thepresence of the cationic antimicrobial agent, despite the presence of acomponent that is known to interact with cationic antimicrobial agent;(ii) the composition improves antimicrobial activity relative to thesame composition without one of either the fatty component or theemollient ester present; or (iii) the composition with less cationicantimicrobial agent present maintains the same activity relative to acomposition with more cationic antimicrobial agent present but lackingone of either the fatty component or the emollient ester; or (iv) thecomposition shows synergistic antimicrobial activity when the cationicantimicrobial agent, fatty component and emollient ester are present.

When applied to the skin, the compositions have rapid bactericidalactivity due to the high concentration of lower alcohol(s) and theenhanced activity of the cationic antimicrobial agent in the presence ofthe fatty component and optionally, the emollient ester. After thecompositions are applied to the skin, the compositions dry quickly asthe lower alcohol evaporates, and a nonvolatile antimicrobialcomposition remains. This nonvolatile composition comprises the cationicantimicrobial agent, fatty component, and optionally, the emollientester. This antimicrobial composition that remains on the skin isnon-irritating and provides persistent bactericidal activity. Inaddition to enhancing the antimicrobial activity, the fatty componentcan also serve as a protectant and prevent premature removal of theantimicrobial composition by washing off with aqueous fluids.

The compositions described herein also contribute to improved adhesionof medical adhesive articles that may be used in the presence of or onthe compositions. Biguanides, such as chlorhexidine gluconate (CHG), aretypically water soluble agents, which can resolubilize in the presenceof moisture and undermine the skin adhesion of medical adhesive articlessuch as dressings, adhesive incise drapes or tapes. This loss inadhesion can result in early failure of the medical adhesive article andplace the patient at increased risk of infection due to, for example,lift of an incise drape at the incisional area or loss of secural of acatheter. The compositions of this invention contribute to improvedadhesive performance of medical adhesive articles primarily as theresult of a fatty component, particularly the fatty alcohols. Theimprovement in adhesion can be an overall increase in adhesive effect,i.e. increased adhesion of the medical adhesive article to skin coatedwith the antimicrobial compositions described herein. The improvement inadhesion can also be a reduction in the variability of adhesiveperformance of the medical adhesive article between patients, resultingin a more universally effective attachment of the medical adhesivearticle in a given patient population. The improvement in adhesion canalso be the prevention of drape lift or loss of adhesion in the presenceof water or saline. This provides a benefit when the compositions areused as preoperative surgical preps with the presence of large amountsof blood and saline in the area of the incision.

The inventors of this application have surprisingly found that that thefatty components enhance the antimicrobial efficacy of cationicantimicrobial agents such as chlorhexidine and its salts, particularlychlorhexidine gluconate. The inventors have also found that thecombination of the fatty components with the emollient esters furthercan synergistically enhance the activity of the compositions. Thus, thecompositions comprise improved overall antimicrobial efficacy comparedto compositions containing cationic antimicrobial agents currentlyemployed in the art.

The fatty components and the emollient esters both function to increasehydrophobicity of the composition. The increased hydrophobicity of thecomposition, after drying on skin, functions to improve adhesion ofmedical articles in the presence of moisture. The hydrophobic nature ofthe compositions also reduce the “wash off” effect of the activecationic agent by hydrophilic or aqueous solutions employed in thehealthcare setting such as sterile saline rinses.

Unexpectedly, neither the hydrophobic fatty component nor the emollientester adversely affect the antimicrobial activity of the composition,and in most cases, improve the antimicrobial efficacy of theantimicrobial composition. This is surprising for several reasons.First, the dilution effect of the fatty component and the emollientester on the cationic antimicrobial agent does not affect theantimicrobial activity of the composition. Thus, lower levels ofcationic antimicrobial agent, particularly CHG, are necessary to producea given antimicrobial efficacy level. This reduction in concentration ofthe cationic antimicrobial agent on the skin can also aid in reducingthe skin irritation possible with compositions containing highconcentrations of CHG. When compositions containing only alcohol, CHG,and water are applied to the skin, the alcohol quickly evaporates offessentially leaving behind a film with a high concentration of CHG,which has the potential to irritate the skin.

Conversely, the increased hydrophobicity due to the fatty component andemollient ester, when used, also allows for increased levels of CHG incompositions, which increases the antimicrobial activity of thecompositions and maintains desirable cosmetic feel while minimizing skinirritation.

Second, when used with chlorhexidine salts, the inventors also foundsurprising that the fatty component, particularly the fatty alcohols,enhanced antimicrobial efficacy. Typical components of knownantimicrobial compositions such as nonionic surfactants or higheralcohols are likely to decrease chlorhexidine activity, as discussed inU.S. Pat. No. 5,017,617. Anionic surfactants are generally incompatibleand may reduce the antimicrobial activity of chlorhexidine salts. Theuse of nonionic surfactants can also have a dramatic effect on theavailability of chlorhexidine salts and their activity. While notwanting to be bound by theory, one explanation may be micellular bindingof the chlorhexidine.

An optimal range of antimicrobial efficacy occurs with increasingaddition of the hydrophobic fatty components and optionally, theemollient ester. At levels higher than the optimal range of either thefatty component alone, or the fatty component combined with theemollient ester, a gradual reduction in antimicrobial efficacy occurs,most likely due to the dilution effect that eventually overwhelms thecationic antimicrobial agent. In a preferred embodiment, the ratio ofnonvolatile hydrophobic components (e.g., the total of the fattycomponent, the optional emollient ester, and other lipids, if any) tothe cationic antimicrobial agent is at least 0.5:1; more preferably 1:1;even more preferably 2:1, and most preferably 3:1.

The antimicrobial efficacy of the composition remains high at ratiosexceeding 6:1, but the increasing levels of fatty component and theoptional emollient ester begin to negatively impact both the cosmeticfeel of the composition and the time to dry (or at least the appearanceof dryness). The emollient esters in particular will contribute an oilylook and feel that may be aesthetically undesirable in use.

When applied, the antimicrobial composition is preferably ahydroalcoholic composition as a solution. At a minimum, the cationicantimicrobial agent, the fatty component and the emollient ester whenused should be soluble at ambient conditions in the lower alcohol andthe hydroalcoholic solvent system.

Lower Alcohol

The alcohol used in the present invention is a lower hydrocarbon chainalcohol such as a C₂-C₅ alcohol. In preferred embodiments the alcohol ischosen from ethanol and isopropanol, and most preferably ethanol.Ethanol is a preferred alcohol based on broad spectrum and quick kill ofmicrobes and an odor acceptable to consumers such as doctors, nurses andclinicians. Propyl alcohol (1-propanol) may also be used.

A blend of two or more lower alcohols may be used as the alcohol contentin the hydroalcoholic solvent system. The lower alcohols may bedenatured, such as for example, denatured ethanol including SDA-3C(commercially available from Eastman Chemical, Kingsport, Tenn.).Co-solvents may be further included in the composition with the loweralcohol. Considering the topical application contemplated for theantimicrobial composition, suitable co-solvents include acetone,hydrocarbons such as isooctane, glycols, ketones, ethers, and shortchain esters.

The C₂-C₅ lower alcohol used in the compositions is used in sufficientamount to dissolve the C₁₂-C₂₁ fatty component and emollient ester. Inmost embodiments, the lower alcohol is present in an amount of at least35 wt-%, and even more preferably at least 50 wt-%, based on the totalweight of the antimicrobial composition.

Compositions having lower alcohol to water ratios within the range 40:60to 95:5 ensure an efficacious immediate bacterial kill. In a preferredembodiment the lower alcohol:water ratio is between about 55:45 and90:10, and more preferably at least 65:35. Increased lower alcohol towater ratios are used in a preferred embodiment for optimumantimicrobial activity and to ensure the composition is fast drying.

A useful concentration of the fatty component and the cationicantimicrobial agent depend on their respective solubilities in a givenhydroalcoholic solvent system. For example, the solubility of CHG in thehydroalcoholic solvent system decreases with increasing C₂-C₅ alcoholconcentration. In contrast, the fatty components may require increasedlevels of C₂-C₅ alcohol concentration to solubilize the fattycomponents. One skilled in the art can readily determine an optimumrange of concentrations based on the solubility of the cationicantimicrobial agent and the fatty component for a given antimicrobialcomposition or a given solvent system.

Fatty Component

The antimicrobial composition includes a fatty component as a cidatropethat provides improved antimicrobial efficacy to the antimicrobialcomposition. The fatty component preferably comprises at least 12 carbonatoms, and most preferably at least 14 carbon atoms. The fatty componentpreferably comprises no more than 21 carbon atoms, and preferably nomore than 18 carbon atoms.

Fatty components suitable for use as a cidatrope in the antimicrobialcompositions include a C₁₂-C₂₁ fatty alcohol, a C₁₂-C₂₁ fatty estercontaining one or more free hydroxyl groups, a C₁₂-C₂₁ fatty ethercontaining one or more free hydroxyl groups, a C₁₂-C₂₁ fatty amidecontaining one or more free hydroxyl groups, and combinations thereof.The fatty components are preferably linear alkyl chains, but branchedalkyl chains may also be used.

The fatty component of the composition is typically the hydrophobiccomponent of the composition that contributes to the improved adhesionof medical adhesive articles to the skin, particularly in the presenceof moisture or fluids. The fatty component is also preferably waxy toimprove the overall cosmetic skin feel of the composition as well.

In a preferred embodiment, the components of the antimicrobialcompositions are not ethoxylated. Ethoxylation affects the moisturesensitivity of the resultant antimicrobial composition, with a resultingdecrease in adhesion performance. If any one of the components isethoxylated, it is preferably no more than one or two moles of ethyleneoxide.

Preferably, the fatty component is present in the composition in anamount of at least 0.5 wt-%, more preferably at least 1 wt-%, even morepreferably at least 2 wt-%, and most preferably at least 3 wt-% based onthe total weight of the antimicrobial composition. In certainembodiments, the fatty component is present in amounts of no more than 6wt-%, and more preferably no more than 5 wt-%. Higher levels can be useddepending on the ratio of cationic antimicrobial agent to totalnonvolatile components in the antimicrobial composition as discussedabove.

Fatty Alcohols

The class of fatty alcohols suitable for use in the compositionsdescribed herein include an alkyl, alkenyl or aralkyl alcohol comprisingat least 12 carbon atoms, and most preferably at least 14 carbon atoms.The fatty alcohol comprises at most 21 carbon atoms, and preferably atmost 18 carbon atoms. The fatty alcohols are preferably primary fattyalcohols, although secondary or tertiary alcohols are also effective.Examples of suitable C₁₂-C₂₁ fatty alcohols include but are not limitedto lauryl alcohol, myristyl alcohol, cetyl alcohol, isostearyl alcohol,isocetyl alcohol, octyl dodecanol, 2-hexyl decanol, and 2-hexyldodecanol. Preferably, the C₁₂-C₂₁ fatty alcohol is a wax at ambientconditions.

Particularly preferred C₁₂-C₂₁ fatty alcohols are myristyl alcohol andcetyl alcohol. Cetyl alcohol or 1-hexadecanol provides enhanced andpreferably synergistic bactericidal activity with cationic antimicrobialagents, and acceptable cosmetic feel when applied topically. Cetylalcohol is safe, non-irritating, and is widely used in pharmaceuticaland drug creams. It also provides water resistance to the formula afterit is applied to the skin, thereby contributing to improved skinadhesion of medical adhesive articles to the composition. In amountsabove 2 wt-% based on the total weight of the antimicrobial composition,the C₁₂-C₂₁ fatty alcohols contribute to improved skin adhesion underwet conditions.

Fatty Esters

The class of fatty esters suitable for use in the compositions areC₁₂-C₂₁ fatty acid esters comprising a C₁₂-C₁₈ branched or straightchain alkyl group, at least one ester linkage, and at least one freehydroxyl group. Preferably, the fatty acid esters are highly pure, i.e.fatty acid monoesters, fatty acid diesters.

A subset of this class suitable for use in the compositions describedherein includes a (C₁₂-C₁₈) saturated or unsaturated fatty acid ester ofa polyhydric alcohol. Preferably, the fatty acid ester is a (C₁₂-C₁₈)saturated fatty acid ester of a polyhydric alcohol. A fatty acid esterof a polyhydric alcohol is preferably of the formula (R¹—C(O)—O)_(n)—R²,wherein R¹ is the residue of a (C₁₂-C₁₆) saturated fatty acid(preferably, a (C₁₂-C₁₆) saturated fatty acid), or a (C₁₂-C₁₈)unsaturated (preferably, a C₁₂-C₁₆) unsaturated, includingpolyunsaturated) fatty acid, R² is the residue of a polyhydric alcohol(typically and preferably, glycerin, and propylene glycol, although awide variety of others can be used including butylene glycols, hexyleneglycols, and diols ), and n=1 or 2. The R² group includes at least onefree hydroxyl group (preferably, residues of glycerin or propyleneglycol). Preferred fatty acid esters of polyhydric alcohols are estersderived from C₁₂, C₁₄, and C₁₆ saturated fatty acids. For embodiments inwhich the polyhydric alcohol is glycerin or propylene glycol, n=1.

Exemplary fatty acid monoesters include, but are not limited to,glycerol monoesters of lauric (monolaurin), myristic, and palmitic acid,and propylene glycol monoesters of lauric, myristic, and palmitic acid.Other fatty acid monoesters include glycerin and propylene glycolmonoesters of oleic (18:1), linoleic (18:2), linolenic (18:3), andarachonic (20:4) unsaturated (including polyunsaturated) fatty acids. Asis generally know, 18:1, for example, means the compound has 18 carbonatoms and 1 carbon-carbon double bond. Preferred unsaturated chains haveat least one unsaturated group in the cis isomer form.

Another subset of fatty acid esters suitable for use as the fattycomponent include (C₁₂-C₂₁) fatty alcohol ester of a (C₂-C₈)hydroxycarboxylic acid (also often referred to as a (C₂-C₈)hydroxycarboxylic acid ester of a (C₁₂-C₁₈) fatty alcohol), a (C₁₂-C₂₂)mono- or poly-unsaturated fatty alcohol ester of a (C₂-C₈)hydroxycarboxylic acid (also often referred to as a (C₂-C₈)hydroxycarboxylic acid ester of a (C₁₂₋₁₈) mono- or poly-unsaturatedfatty alcohol). The hydroxycarboxylic acid moiety can include aliphaticand/or aromatic groups. For example, fatty alcohol esters of salicylicacid are possible.

The hydroxyacids typically have one hydroxyl group and one carboxylicacid group. They are preferably selected from alpha- andbeta-hydroxyacids including lactic acid, mandelic acid, glycolic acid,salicylic acid, and hydroxybutanoic acid. The fatty alcohols are mostpreferably straight or branched alkyl alcohols having 12 to 18 carbonatoms, and most preferably 12 to 16 carbon atoms or a (C₁₂-C₂₀)unsaturated fatty alcohol (preferably, a C₁₂-C₁₈) unsaturated, includingpolyunsaturated, fatty alcohol). Examples of fatty alcohols includelauryl, myristyl, cetyl, and their derivatives.

Exemplary fatty alcohol monoesters of hydroxycarboxylic acids include,but are not limited to; C₁₂-C₁₅ alkyl lactates, lauryl lactate, myristyllactate, cetyl lactate, and isostearyl lacatate.

Fatty Ethers

The class of fatty ethers suitable for use in the compositions areC₁₂-C₂₁ fatty acid ethers comprising a C₁₂-C₁₈ branched or straightchain alkyl group, at least one ether linkage, and at least one freehydroxyl group. A subset of fatty ethers suitable for use in theantimicrobial compositions include a (C₁₂-C₁₈) saturated or unsaturatedfatty ether of a polyhydric alcohol. Preferably, the fatty ether is a(C₁₂-C₁₆) saturated fatty ether of a polyhydric alcohol.

A fatty ether of a polyhydric alcohol is preferably of the formula(R³—O)_(n)—R⁴, wherein R³ is a (C₁₂-C₁₈) saturated aliphatic group(preferably, a (C₁₂-C₁₆) saturated aliphatic group), or a (C₁₂-C₁₈)unsaturated (preferably, (C₁₂-C₁₆) unsaturated, includingpolyunsaturated) aliphatic group, R⁴ is the residue of glycerin,butylene glycol, or propylene glycol, and n=1 or 2. For glycerin andpropylene glycol n=1. Preferred fatty ethers are monoethers of (C₁₂-C₁₈)alkyl groups (more preferably, (C₁₂-C₁₆ alkyl groups).

Exemplary fatty monoethers include, but are not limited to, laurylglyceryl ether and lauryl propylene glycol ether. Other fatty monoethersinclude glycerin and propylene glycol monoethers of oleyl (18:1),linoleyl (18:2), and linolenyl (18:3) unsaturated and polyunsaturatedfatty alcohols. In certain preferred embodiments, the fatty monoethersthat are suitable for use in the present composition include laurylglyceryl ether, myristyl glycerylether, lauryl propylene glycol ether,cetyl propylene glycol ether, and combinations thereof. Unsaturatedchains preferably have at least one unsaturated bond in the cis isomerform.

Emollient Esters

In preferred embodiments, the antimicrobial composition also includes anemollient ester as a cidatrope that provides improved antimicrobialefficacy to the antimicrobial composition. In most embodiments, theemollient ester preferably comprises a total of at least 8 carbon atoms,preferably comprises no more than 20 carbon atoms, and comprises atleast two ester linkages.

The emollient esters used in this invention may serve more than onepurpose. They may serve to prevent skin irritation and drying, improvethe cosmetic feel of the formulation, enhance the antimicrobial activityof the formulation, and moisturize the skin by reducing watertransmission. When used at higher concentrations, the emollient estersmay also enhance the dry adhesion of medical adhesive articles.

The emollient ester is generally a liquid at room temperature and haspoor solubility in water, i.e., soluble in water at 23° C. in amountsless than 2 wt-%. Emollient esters suitable for use as a cidatrope inthe antimicrobial compositions are selected from diesters of bibasicacids, diesters of diols, triesters of citric acid, and triesters oftriols. Preferred diesters of bibasic acids include dibutyl adipate,diisopropyl adipate, diisobutyl adipate, dihexyl adipate, diisopropylsebacate, dibutyl sebacate and mixtures thereof. In a similar manner,preferred triesters of citric acid include tributyl citrate. Preferreddiesters of diols include esters of butanediol and hexanediol. Diestersof propylene glycol such as propylene glycol dicaprylate may also beuseful. The most preferred emollient esters are diisopropyl adipate,dibutyl adipate, and tributyl citrate.

Preferably, the emollient ester is present in the composition in anamount of at least 0.5 wt-%, more preferably at least 1 wt-%, and mostpreferably at least 2 wt-%. In preferred embodiments, the emollientester is present in amounts of no more than 6.0 wt-%, more preferably nomore than 5 wt-%. Higher levels can be used depending on the ratio ofcationic antimicrobial agent to total nonvolatile components asdiscussed above.

Cationic Antimicrobial Agent

The cationic antimicrobial agent is that component of the compositionthat provides at least part of the antimicrobial activity. That is, thecationic antimicrobial agent has at least some antimicrobial activityfor at least one microorganism. It is generally considered the mainactive component of the compositions described herein. The cationicantimicrobial agent includes an effective amount of one or moreantimicrobial agents selected from the group consisting of biguanidesand bisbiguanides such as chlorhexidine and its various salts includingbut not limited to the digluconate, diacetate, dimethosulfate, anddilactate salts, as well as combinations thereof; polymeric quaternaryammonium compounds such as polyhexamethylenebiguanide; small moleculequaternary ammonium compounds such as benzalkonium halides; andcompatible combinations thereof. It is particularly important, however,with cationic antimicrobial agents in a salt form to use a counter ionthat ensures solubility in aqueous fluid above the minimum inhibitoryconcentration (MIC) of the treatment organism. If the solubility limitis less than the MIC, treatment may be ineffective.

The cationic component is at least 10 wt-%, more preferably 15 wt-%,based on the total weight of the nonvolatile components in thecomposition. The cationic antimicrobial agent is preferably no more than70 wt-%, and more preferably no more than 50 wt-%, based on the totalweight of nonvolatile components in the composition.

Based on the total weight of the antimicrobial composition, cationicantimicrobial agents are typically used at levels of at least 0.05% byweight, preferably at least 0.1% by weight and most preferably at least0.25% by weight and most preferably at least 0.5% by weight. Compoundsof this class are preferably used at levels less than about 8%, morepreferably less than about 6%, and most preferably less than about 4% byweight of the composition.

The classes of cationic antimicrobial agent suitable in the presentinvention are discussed further below.

Biguanides

This class of antimicrobials is represented by the formula:

R—NH—C(NH)—NH—C(NH)—NH(CH₂)_(n)NHC(NH)—NH—C(NH)—NH—R

Where n=3-10, preferably 4-8, and most preferably 6; and R═C₄-C₁₈branched or straight chain alkyl optionally substituted in availablepositions by halogen or C₆-C₁₂ aryl or alkaryl optionally substituted inavailable positions by halogen.

The preferred compound of this class is chlorhexidine. This may bepresent as the free base but is preferably present as a disalt ofacetate, gluconate, lactate, methosulfate (CH₃OSO₃ ⁻), or a halide orcombinations thereof. The most preferred compound is chlorhexidinedigluconate (CHG). Other anions may be useful. Many salts ofchlorhexidine have high solubility (>1 g/100 mL) in alcohol/watersystems and are therefore useful in compositions of this invention.

The antimicrobials of this class are particularly preferred informulations that are aqueous and protected from light. This is believedto reduce the degradation of the compound. When used in compositionscomprising less than about 20% by weight water, antimicrobial agents ofthis class may also include a hydrophilic solvent that solubilizes theantimicrobial agent. Examples of suitable solvents for chlorhexidinegluconate include glycols (compounds having at least two hydroxyl groupsper molecule) such as PEGs having a molecular weight below 2000 andpreferably less than 1000 and most preferably less than about 800daltons; glycerin and polyglycerols, propylene glycol, dipropyleneglycol, tripropylene glycol, polypropylene glycol, ethyleneoxide/propylene oxide random or block copolymers, trimethylolpropane,pentraerithiritol, sorbitol, panetothenol, glucuronolactone, gluconicacid, and the like as well as other polar solvents such as N-methylpyrrolidone, propylene carbonate, butyrolactone and the like. When used,the solubilizing solvent should be present in sufficiently low amountsto minimize sensitivity to water. Preferably, the solubilizing solventis present in amounts less than 1 wt % relative to the weight of thetotal antimicrobial composition.

Care must also be taken when formulating chlorhexidine as well as othercationic antimicrobial compounds to avoid inactivation by sequesteringit in micelles which may be formed by incorporation of surfactantsand/or emulsifiers. Preferred compositions of this invention areessentially free of surfactants and/or emulsifiers.

Bis(biguanide)s such as chlorhexidine are very basic and capable offorming multiple ionic bonds with anionic materials. For this reason,biguanide-containing compositions are preferably free of anioniccompounds that can result in precipitation of the antimicrobial. Anionicsurfactants useful, for example, as wetting agents, may also need to beavoided. Halide salts may need to be avoided. For example, chlorhexidinedigluconate (CHG) will precipitate rapidly in the presence of halidesalts above a concentration of about 0.1M. Therefore, if a systemincludes CHG or other antimicrobial of this class, and needs to comprisesalts for stability or other purposes, preferably gluconate salts suchas triethanolamine gluconate or sodium gluconate, are used.

Polymeric Quaternary Amine Compounds

Antimicrobial polymers comprising quaternary amine groups may also beused as the cationic antimicrobial agent in the compositions describedherein. These are typically polymers having quaternary amine groups withat least one alkyl or aralkyl chain of at least 6 carbon atoms andpreferably as least 8 carbon atoms. The polymers may be linear,branched, hyperbranched or dendrimers. Preferred antimicrobial polymericquaternary amine polymers include those described in U.S. Pat. Nos.6,440,405; 5,408,022; and 5,084,096; PCT Publication No. WO/02102244;and Disinfection, Sterilization and Preservation, S. Block, 4^(th) ed.,1991, Chapter 13, Lea & Febiger.

A particularly preferred class of polymeric quaternary ammoniumantimicrobial compounds are polybiguanides. Compounds of this class arerepresented by the formula:

X—R¹—NH—C(NH)—NH—C(NH)—NH—R²—NHC(NH)—NH—C(NH)—NH—R³—X

Where R¹, R², and R³ are bridging groups such as polymethylene groupspreferably having 2 to 10 methylene groups, more preferably 4 to 8methylene groups and most preferably 6 methylene groups. The methylenegroups can be optionally substituted in available positions withhalogen, hydroxyl, or phenyl groups. X is a terminal group and istypically an amine, amine salt, or a dicyandiamide group. The preferredcompound of this class is polyhexamethylene biguanide (PHMB)commercially available as Cosmocil CQ from Aveci, Wilmington, Del.

Poly(biguanide) antimicrobials such as PHMB are very basic and arecapable of forming multiple ionic bonds with anionic materials. For thisreason, biguanide-containing compositions are preferably free of anioniccompounds that can result in precipitation and/or inactivation of theantimicrobial. Anionic surfactants useful, for example, as wettingagents, may also need to be avoided. Halide salts also may need to beavoided.

Small Molecule Quaternary Ammonium Compounds

This class of compounds typically comprise one or more quaternaryammonium groups wherein attached to the quaternary ammonium group is atleast one C₆-C₁₈ linear or branched alkyl or aralkyl chain. Suitablecompounds include those disclosed in Disinfection, Sterilization andPreservation, S. Block, 4^(th) ed., 1991, Chapter 13, Lea & Febiger.Particularly preferred compounds of this class have one or two C₈-C₁₈alkyl or aralkyl chains and may be represented by the following formula:

R¹R²NR³R⁴⁺X⁻

Where R¹ and R² are C1-C18 linear or branched alkyl, alkaryl, or aralkylchains that may be substituted in available positions by N, O, or Sprovided at least one R¹ or R² is a C₈-C₁₈ linear or branched alkyl,alkaryl, or aralkyl chains that may be substituted in availablepositions by N, O, or S. R³ and R⁴ are C₁-C₆ alkyl, phenyl, benzyl, orC₈-C₁₂ alkaryl groups. R³ and R⁴ may also form a ring such as a pyridinering with the nitrogen of the quaternary ammonium group. X is an anion,preferably a halide, and most preferably C₁— or Br—. Other anions mayinclude methosulfate, ethosulfate, phosphates and the like. Preferredcompounds of this class include mnoalyltrimethylammonium salts,monalkyldimethylbenzyl ammonium salts, dialkyldimethyl ammonium salts,benzethonium chloride, and octenidine.

Examples of preferred quaternary ammonium antiseptics includebenzalkonium halides having an alkyl chain length of C₈-C₁₈, morepreferably C₁₂-C₁₆, and most preferably a mixture of chain lengths. Forexample, a typical benzalkonium chloride sample may be comprise of 40%C₁₂ alkyl chains, 50% C₁₄ alkyl chains, and 10% C₁₆ alkyl chains. Theseare commercially available from numerous sources including Lonza(Barquat MB-50). Benzalkonium halides substituted with alkyl groups onthe phenyl ring are also suitable. A commercially available example isBarquat 4250 available from Lonza. Dimethyldialkylammonium halides wherethe alkyl groups have chain lengths of C₈-C₁₈ are also suitable. Amixture of chain lengths such as mixture of dioctyl, dilauryl, anddioctadecyl may be particularly useful. Exemplary compounds arecommercially available from Lonza as Bardac 2050, 205M and 2250 fromLonza; Cetylpyridinium halides such as cetylpyridinium chlorideavailable from Merrell labs as Cepacol Chloride; Benzethonium halidesand alkyl substituted benzethonium halides such as Hyamine 1622 andHyamine 10× available from Rohm and Haas; octenidine and the like.

Optional Ingredients

The compositions of the present invention may optionally includeingredients such as salts, humectants (in minimal amounts due to theirhydrophilic nature and affect on moisture sensitivity), stabilizers,other antimicrobials, fragrances, therapeutic agents, propellants, dyes,solvents, other emollients, polymers, conditioning agents, and vitamins.Preferred solvents include acetone, dimethylisosorbide, and isooctane.

Preferably, the formulations are essentially free of surfactants. Mostpreferably, the compositions do not contain surfactants in anymeasurable quantity. Surfactants increase the water sensitivity of theformulations when applied on the skin and decrease adhesive performance.If present, the surfactants preferably have an HLB (hydrophilic tolipophilic balance) less than 6, more preferably less than 4. Examplesof surfactants include glycerol palmitate, poloxamers, polyglycerolesters, PEG-esters, and sorbitan esters.

Preferably the compositions are essentially free of hydrophilic polymersand water-soluble polymers. Polymeric thickeners such as ethyl cellulosemay be used preferably in amounts less than 1 wt-%.

It should be noted that certain fatty components of the fatty acid esterclass as well as the emollient esters are amphiphiles and may be surfaceactive. For example, certain alkyl monoglycerides described herein aresurface active. For certain embodiments of the invention, the fattycomponent and emollient ester component is considered distinct from a“surfactant” component.

Methods of Formulation

When formulating compositions described herein, it is desirable to havethe C₁₂-C₂₁ fatty component as the waxy component and the emollientester as a liquid. As used herein, “wax” or “waxy” refers to a componenthaving a melt temperature greater than 23 deg C. By using a combinationof the two, the resulting compositions have more elegant skin feel anddry quickly. For example, most emollient esters present without thefatty component in the composition above concentrations of 0.5% (w/w)would be slow to dry and leave an undesirable oily film on the skin whenapplied topically. By incorporating a fatty component into thecomposition, the composition dries faster, loses its oily feel, andbecomes cosmetically acceptable.

Furthermore, by using a combination of the fatty component and theemollient ester, the amount of each component that can be used in theformula is much greater than if either were used alone. Using greateramounts of either the fatty component or emollient ester is highlydesirable, because increasing the concentration of either componentincreases the antimicrobial efficacy of the composition. By using both afatty component and an emollient ester, the compositions show bothdesirable skin feel and improved antimicrobial efficacy. Increasing theconcentration of the fatty component is particularly preferred becausethe fatty component contributes to increased wet adhesion performance aswell.

Generally, the fatty component/emollient ester ratio in compositionsdescribed herein is about 5:1 to 1:5. Preferably, the ratio is greaterthan 1:2, and most preferably about 1:1. Preferably, both the fattycomponent and emollient ester are soluble in the lower alcohol/watersolution and do not precipitate over time. Most preferably, the fattycomponent is a wax at ambient temperature. Without being bound to aparticular theory, it is believed that the fatty alcohols and emollientesters interact with the outer cellular membranes of bacteria in such amanner that synergistically enhances the activity of the cationicantimicrobial agent.

The compositions of this invention are especially useful forpreoperative surgical, catheter, and IV antiseptic preps. They can alsobe useful for preventing or reducing catheter-related bloodstreaminfections. For these formulations, enhanced wet adhesion and enhancedantimicrobial efficacy are two advantages that are important. Preferredformulations according to the invention for these preps contain asignificant amount of fatty component, preferably greater than 2 wt %,most preferably greater than 2.5 wt %. Ideally, the fatty componentshould be as hydrophobic as possible and waxy (with a melting pointgreater than 23° C.) in order to enhance the adhesion of dressings inwet conditions. Preferred fatty components include myristyl and cetylalcohol and derivatives thereof.

Preferred compositions would also contain an emollient ester, which isnon-comedolytic (does not block skin pores) and further providesenhanced antimicrobial efficacy. Preferred emollient esters according tothe invention for catheter and IV preps include diisopropyl adipate,dibutyl adipate, and tributyl citrate at concentrations greater than 1wt %, and preferably greater than 1.5 wt %. The compositions alsocontain about 2% (w/w or w/v) chlorhexidine gluconate to meet Center forDisease Control (CDC) guidelines for preventing cathether-related bloodstream infections. They would also comprise a majority amount of C₂-C₅alcohol, preferably greater than 65 wt-%, so that the formulation willdry quickly after topical application. Catheter prep compositions willalso preferably contain no humectants or other water soluble materials(including surfactants), which could undermine dressing adhesion underwet conditions. This is particularly important because small amounts ofsurfactants, especially fatty alcohol ethoxylates, can significantlyundermine adhesion in the presence of moisture including sweat, saline,blood, and water. Small amounts of humectants such as glycols orglycerol may be used in some embodiments of the compositions, but mostcompositions are preferably free of humectants.

The compositions of this invention are also useful for hand antisepticsand surgical scrubs. For this application, adhesion of medical adhesivearticles may be less significant but enhanced efficacy and superior skinfeel are very important. For hand antiseptics, the compositions willpreferably contain greater than 60 wt % lower alcohol and about 2 to 8wt % of hydrophobic components comprising a fatty component andemollient ester. Humectants may also be used as moisture sensitivity ofthe compositions is less critical in hand antiseptic applications. Mostpreferably, the compositions will contain greater than 70 wt % alcoholto provide an immediate and significant reduction of transient andnormal flora of the hands. In addition, the compositions would comprisepreferably 0.3 to 1.5 wt % of a nonvolatile antimicrobial cationicagent, and most preferably 0.4 to 1.0 wt %. In these compositions, thepreferred fatty components are waxy and used at levels of 1 to 4 wt %.

One or more fatty components can be used including fatty components withtwo hydroxyl groups such as glycerol monolaurate or glycerolmonomyristate. Because water sensitivity is less important in handantiseptic applications, a large variety of fatty components can bepotentially used. Preferably, the compositions also contain a lightfeeling, liquid emollient ester such as tributyl citrate or diisopropyladipate and a small amount of humectant. Using the combination of a waxyfatty component and liquid emollient ester results in superior skin feelcompared to compositions containing only one of these components alone.Furthermore, the use of both components together allows for the use ofhigher concentrations of both the fatty component and emollient ester.Furthermore, the use of higher concentrations of these componentscounteracts the drying effect and irritation of the skin caused by thelower alcohol in these compositions especially with repeatedapplication. Lower alcohols (such as ethanol) by themselves are known tobe drying especially at higher concentrations. Optionally, theformulations may contain other emollients such as higher molecularweight waxes and oils that do not enhance antimicrobial efficacy, butlower the transepidermal water loss (TEWL) of skin.

The compositions of this invention are also useful for preventing andtreating skin infections. The compositions may be used to preventsurgical site infection by applying the compositions to the skin priorto surgery. When the compositions contain chlorhexidine gluconate, theskin may be preferably treated topically less than about 30 hours priorto surgery, and most preferably less than 10 hours prior to surgery.These compositions can be applied to reduce the transient and normalflora of the skin. Repeated applications may be used to provide evenhigher efficacy (log reduction of bacteria) on the skin. In a preferredembodiment, the formulations are used a preoperative surgical prep orskin antiseptic.

Likewise, the compositions of this invention can be used to preventcatheter-related bloodstream infections. Specifically, the compositionsare applied topically to the skin for 30-180 seconds and allowed to dryfor 30-180 seconds or for a time period such that the alcoholevaporates. The remaining layer of nonvolatile components surprisinglyprovide enhanced antimicrobial activity that is persistent for longperiods of time. After the composition is applied and visually dry, acatheter or intravenous line can be inserted and secured with atransparent dressing. The nonvolatile components remain under thedressing as a highly active, persistent bactericidal layer on the skin.

The compositions can be used in the treatment and/or prevention ofafflictions that are caused, or aggravated by, microorganisms (e.g.,Gram positive bacteria, Gram negative bacteria, fungi, protozoa,mycoplasma, yeast, viruses, and even lipid-enveloped viruses) on skinand/or mucous membranes, such as those in the nose (anterial nares,nasopharangyl cavity, nasal cavities, etc.), outer ear, and mouth,rectum, vagina, or other similar tissues. Particularly relevantorganisms that cause or aggravate such afflications includeStaphylococcus spp., Streptococcus spp., Pseudomonas spp., Enterococcusspp., and Esherichia spp., bacteria, as well as herpes virus,Aspergillus spp., Fusarium spp. Candida spp. as well as combinationsthereof. Particularly virulent organisms include Staphylococcus aureus(including resistant strains such as Methicillin ResistantStaphylococcus Aureus (MRSA), Staphylococcus epidermidis, Streptococcuspneumoniae, Enterococcus faecalis, Vancomycin Resistant Enterococcus(VRE), Pseudomonas auerginosa, Escherichia coli, Aspergillus niger,Aspergillus fumigatus, Aspergillus clavatus, Fusarium solani, Fusariumoxysporum, Fusarium chlamydosporum, Candida albicans, Candida glabrata,Candida krusei, and combinations thereof.

Compositions of the present invention can be used for the preventionand/or treatment of one or more microorganism-caused infections or otherafflictions. In particular, compositions of the present invention can beused for preventing and/or treating one or more of the following: skinlesions, conditions of the skin such as impetigo, eczema, diaper rash ininfants as well as incontinent adults, inflammation around ostomydevices, shingles, and bacterial infections in open wounds (e.g., cuts,scrapes, burns, lacerations, chronic wounds); necrotizing faciitis;infections of the outer ear; vaginal yeast infections; bacterialrhinitis; ocular infections; cold sores; genital herpes; colonization byStaphylococcus aureus; tinea pedis (i.e., athlete's foot); tinea curis(i.e., jock itch); tinea corporis (i.e., ringworm); candidiasis; strepthroat, strep pharyngitis, and other Group A Streptococci infections;rosacea (often called adult acne); psoriasis; and burns. In sum,compositions of the present invention can be used for preventing and/ortreating a wide variety of topical afflictions caused by microbialinfection (e.g., yeast, viral, bacterial infections).

The compositions are particularly useful because lower alcohols and someof the fatty components are known skin penetration enhancers and candeliver the nonvolatile components to deeper layers of the skin.Furthermore, the lower alcohol can disinfect the skin as well providingan immediate log reduction of microorganisms on skin.

Methods of Application

The compositions can be applied using a variety of techniques includingbut not limited to: foamed applicators, cotton swabs, saturated swabsticks, saturated wipes, aerosols, sprays, brushes, and dips.Preferably, the compositions are contacted with the skin or inanimateobject for 15 to 180 seconds and then allowed to dry. They may be usedas a paint or as a surgical scrub. Because of the unique characteristicsof the inventive compositions, the compositions are particularly usefulfor infection prevention products such as a preoperative antisepticsurgical preparations and antiseptic skin preparations used prior tocatheterization. These compositions are particularly useful when used inconjunction with medical adhesives, tapes, surgical drapes, andtransparent dressing under wet or suboptimal conditions.

Since many of the compositions of the present invention containantimicrobials, it is important that they be dispensed in an efficaciousand precise amount. The compositions of the present invention can bedispensed in a discreet, substantially uniform amount using thedispensers disclosed in U.S. Pat. No. 5,897,031, and U.S. Pat. No.5,799,841.

Methods of Preparation

The compositions of the present invention may be prepared by a varietyof techniques. For example, the process can often be as simple as addingheating the lower alcohol, adding the fatty component and mixing untildissolved, adding the remaining components, followed by the cationicantimicrobial agent.

The processing variables including amount and intensity of high shearmixing, rate of cooling, and order of addition are easily determined byone skilled in the art.

Test Methods Skin Adhesion Test Protocol

Volunteer human test subjects were used for the Skin Adhesion Testing.The subjects' backs were washed with a diluted Ivory soap, rinsed anddried well. The test compositions were applied to their backs by simplypainting the site with gauze saturated with the test composition usingmoderate pressure three times in a continuous circular motion. Afterallowing the test composition to dry, 1 inch×3 inch (2.54 cm×7.6 cm)strips of 3M IOBAN 2 Antimicrobial Incise Drape were very gently appliedover the dry composition. Within 5 minutes the samples were rolled witha 4.5-lb (2.1-kilogram (kg)), 2-inch (5.1 cm) roller to ensure uniformapplication pressure and to simulate conditions in surgery. After thedrape was applied, there was a 5 minute waiting period. A piece of gauze(large enough to cover the sample) soaked with saline was applied,followed by another 5 minute waiting period. An additional 3 mL ofsaline was added to the gauze followed by another 5 minute waitingperiod. The gauze was removed from the samples. The incise drape stripwas removed using a force-measuring instrument at a peel angle of 90degrees to the skin and at a peel rate of 12 inches (30.5 cm) perminute. The average peel force was calculated based on twenty testsacross ten subjects (two per subject). The average peel force requiredto remove the sample was recorded.

Direct Innoculation Filter Assay

This is an in vitro assay using filter paper to compare the residualefficacy of different surgical skin prep formulations.

Phosphate Buffered Water solution (PBW) was made by making a 0.25M stocksolution by putting 34 grams KH₂PO₄ into 500 mL of DI water, adjustingthe pH to 7.2 with 10N NaOH, and adding enough DI water to make 1 liter.The solution was filtered, sterilized, dispensed into a 1 liter sterilebottle, and stored under refrigeration. Butterfield's PBW was made byadding 1.25 mL of the stock solution to 900 mL of DI water and addingneutralizers, stirring, heating to dissolve the components, and dilutingto 1 liter with DI water. The solution was mixed well, dispensed intotwo 500-mL bottles. The bottles containing the solution were autoclavedfor 25 minutes at 121 degree C. The contents were carefully swirledafter removing the bottles from the autoclave.

A Standard Sampling Solution (SSS) was prepared which contained: 0.4grams KH₂PO₄, 10.1 grams Na₂HPO₄, 1.0 gram TRITON X-100 surfactant, 3.0grams lecithin, 30.0 grams TWEEN 80, and deionized water to bring thetotal volume to 1 liter.

Additional solutions and materials included: 24 hour growth plate of E.faecalis; ATCC #10741; Tryptic Soy Agar (TSA); 0.5 McFarlandEquivalenceTurbidity standard, available from Remel of Lenexa, Kans.;sterile disposable dilution tubes, available from Becton Dickenson & Co.Franklin Lakes N.J.; Whatman No. 54 filter paper, cut into 15 mmdiameter circles, Whatman International, Ltd., Maidstone, England;sterile round microscope cover slips, available from VWR Scientific,Inc. of Media Pa.; microscope slides, available from VWR; sterileforeceps; 70% Isopropyl Alcohol (IPA); sterile disposable petri plates,available from VWR; sterile 50 mL centrifuge tubes available from BectonDickenson & Co. Franklin Lakes N.J.; digital timers; pipets andpipettors of appropriate volumes.

A stock suspension of E. faecalis was prepared by adding colonies totest tube containing PBW. Using the 0.5 McFarland EquivalenceTurbidityStandard, the suspension was brought to approximately 1.5×10⁸. Serialdilutions were performed to achieve 10⁻⁶ and plate in duplicate 10⁻⁶ and10⁻⁷. For each Example preparation or control (70% IPA), a microscopeslide was wiped with 70% IPA and placed in the bottom of a petri dish.Using sterile foreceps, two sterile 18 mm round cover slips were placedside-by-side on the slide, and then a 15 mm round cut Whatman filterdisc was placed on each of the round cover slips.

Onto each filter disc was pipetted 25 μL of each Example preparation orcontrol. These discs were allowed to dry for 10 minutes. After 10minutes of dry time, 25 μL of stock suspension of E. faecalis waspipetted onto each filter. The inoculum was left on the filters for 5minutes. After the 5 minute inoculum exposure time, sterile forecepswere used to place each cover slip and filter disc into a 50 mLcentrifuge tube containing 20 mL SSS solution. Each Example or controlwas vortexed in the centrifuge tubes for 2 minutes. Next, 100 μL of eachExample or control was diluted in a dilution tube containing 9.9 mL PBW,to yield a 10⁻² dilution. Serial dilutions were repeated to achieve a10⁻⁴ dilution. Dilutions were plated in duplicate with TSA using pourplate methods and incubated for 48 hours at 35° C. After 48 hours,colonies were counted and recorded.

The CFU/mL was determined by multiplying CFU count by dilution rate. TheCFU/sample was calculated by multiplying the CFU/mL by 20, the amount ofthe SSS dilution. The log₁₀ of the CFU/sample was calculated. This wasthe Log Recovery for each sample. The log recovery values were averagedfor the replicates of each sample (Example) and control. The logrecovery value of each Example was subtracted from the log recovery ofthe control. The result is the log reduction for that Examplepreparation. The log recovery of control was verified as statisticallyequal to calculated inoculum amount, based on enumeration of stocksuspension. Unless stated otherwise, log reduction values reported beloware the average of duplicate preparations.

Skin Panel Evaluation

The purpose of this study was to assess the antimicrobial efficacy ofselected Example formulations, which represent embodiments of theinvention and an alcohol/CHG comparative example. The reduction ofnormal skin flora on backs at was measured 10 minutes post prep.

Two weeks (14 days) prior to the Study Day, human test subjects followeda washout procedure by refraining from using antimicrobial soaps &shampoos, lotions (on the back) and topical and systemic antibiotics;refraining from using chemically treated hot tubs, whirlpools, swimmingpools and tanning beds; refraining from adhesive back panel evaluationsand/or antimicrobial or antiseptic back panel evaluations; refrainingfrom showering or tub bathing the back (the subject may sponge bathe) 24hours prior to the study. If clipping was required the subject returnedto the panel facility a minimum of 48 hours prior to Study Day.

On The Study Day the “Study Day Questionnaire” was completed whichdetermined if the subject had been compliant with the washout proceduresand was still eligible for participation. A randomization scheme foreach back determined location of baseline sampling and treatment(prepped) test sites. Baseline sampling of skin flora was done using theWilliamson-Kligman cup scrub technique. Each prep formulation wasapplied to the appropriate test site with a sponge using a back andforth motion for 30 seconds covering an approximate 2 inch×2 inch area.Prepped sites were allowed to dry and post treatment skin samples weretaken at 10 minutes (±1 min) using the Williamson-Kligman cup scrubtechnique. Timing for sample collection began after application.

The neutralization subject washout was for 7 days and was not requiredto refrain from showering or tub bathing 24 hours before the test day.The samples were collected using the Williamson-Kligman cup scrubtechnique.

Willimson-Kligman Cup Scrub Technique

A sterile scrub cup was placed on the desired skin site and held firmlyto the skin. 2.5 mL of sampling solution was pipetted into the cup andthe area was scrubbed with moderate pressure for 1 minute using asterile Teflon policeman. The sampling solution was removed and placedin a sterile test tube. An additional 2.5 mL of fresh sampling solutionwas pipetted into the cup. The scrub was repeated and this solution waspooled with the first. Bacteria in the sample were enumerated using thepour plate technique following serial dilutions in phosphate bufferedwater. Plates were incubated at 35° C.±2° C. for 72±4 hours. ColonyForming Units (CFUs) were counted and bacteria enumerated using standardmethods.

The sampling solution for skin scrubbing consisted of phosphate buffer(0.04% KH₂PO₄, 1.01% Na₂HPO₄) containing 0.1% Triton X-100, 3.0% Tween80, and 0.3% Lecithin, adjusted to pH 7.9±0.1. The adequacy and efficacyof the neutralizers in these solutions was validated by an in vitromethod prior to study conduct.

Examples

The following non-limiting Examples are provided to illustrate featuresof the invention but are not intended to limit the scope of theinvention. All percent amounts are percent weight/weight (% wt/wt)unless otherwise noted.

TABLE 1a Components Trade/Abbrev. Name Description Supplier/Manf. Manf.Location Acetone Acetone EMD Chemicals, Inc. Gibbstown, NJ ATBC AcetylTributyl Citrate Morflex Inc. Greensboro, NC ATEC Acetyl TriethylCitrate, NF Morflex Inc. Greensboro, NC Cetyl OH Cetyl alcohol or SasolNorth America Westlake, LA 1-hexadecanol CHG 20% Chlorhexidine Medichem,S. A, Paramus, NJ Gluconate solution distributed by George Uhe Company,Inc. Citric Acid Citric Acid MCB Reagents Rahway, NJ DBA Dibutyl adipateAlzo International Sayreville, NJ DBS Dibutyl sebacate Morflex Inc.Greensboro, NC DIPA Diisopropyl adipate Alzo International Sayreville,NJ DIPS Diisopropyl sebacate Alzo International Sayreville, NJ DisodiumNa₂HPO₄, ACS grade EMD Chemicals, Inc. Gibbstown, NJ phosphate DGEdodecyl glyceryl ether Sigma-Aldrich Co. St. Louis, MO EtOH Ethylalcohol, USP 200 Aaper Alcohol Shelbyville, KY proof Ethocel 100Ethylcellulose polymer Dow Chemical Co. Midland, MI E. faecalisEnterococcus faecalis ATCC Manassas, VA (ATCC #10741) FD&C Blue No. 1FD&C Blue No. 1 food safe Sensient Technologies Milwaukee, WI dyeCorporation GDL Glucono-delta-lactone (D- Archer Daniels Decatur, ILGluconic acid) Midland Co. Glycerin Glycerin USP Procter & GambleCincinnati, OH Chemicals Glycerol Glycerol Dow Chemical Co. Midland, MIGML Glycerol monolaurate Med-Chem Labs Galena, IL IPA Isopropyl alcoholEMD Chemicals, Inc. Gibbstown, NJ IPP Isopropyl palmitate AlzoInternational Sayreville, NJ Iso-Cetyl OH Iso-Cetyl alcohol JarchemIndustries Newark, NJ (Jarcol I-16) Inc. Lecithin Refined LecithinAlfaAesar Ward Hill, MA Myristyl OH Myristyl Alcohol Sasol North AmericaWestlake, LA Myristyl lactate Myristyl lactate ISP (International Wayne,NJ Specialty Products) Permethyl 97A Isooctane Chesham SpecialityHarrow, UK Ingredients Ltd Permethyl 99A Isododecane Chesham SpecialityHarrow, UK Ingredients Ltd PHMB polyhexamethylene Arch UK BiocidesCastleford, UK biguanide, (Cosmocil 100) PVP Polyvinyl pyrrolidone K90ISP (International Wayne, NJ 100% powder: 1,300,000 Specialty Products)weight average molecular weight (Mw) in Daltons TBC Tributyl citrateMorflex Inc. Greensboro, NC TEC Triethyl citrate, NF Morflex Inc.Greensboro, NC Triton X-100 C₁₄H₂₂O(C₂H₄O)_(n) is a Shelton Scientific,Inc. Shelton, CT nonionic surfactant; Molecular Biology Certified TSATryptic soy agar; Soybean Becton Dickinson & Sparks, MD Casein DigestAgar Co. Tween 80 Polyoxyethylene (20) JT Baker Philliopsburg, NJsorbitan monoleate (Mallinckrodt Baker, Inc.)

TABLE 1b Components used in Tables 7b, 9b, 10b and 12b Trade/Abbrev.Name Description Supplier/Manf. Manf. Location Cetyl OH Cetyl alcohol orM. Michel and New York, NY 1-hexadecanol Company, Inc. CHG 20%Chlorhexidine Xttrium Laboratories Chicago, IL Gluconate solution DIPADiisopropyl adipate; ISP; International Wayne, NJ (Ceraphyl ® 230)Specialty Products DIPS Diisopropyl sebacate JEEN InternationalFairfield, NJ Corp. DGE Dodecyl glyceryl ether; Phoenix Chemical, IncSomerville, NJ SC50 Skin Care Additive EtOH Ethyl alcohol; ethanol, USPSpectrum Chemicals Gardena, CA 200 proof and Lab Products GlycerolSuperol Glycerine USP Procter & Gamble Cincinnati, OH Chemicals GMLGlycerol monolaurate Med-Chem Labs Galena, IL Myristyl OH MyristylAlcohol M. Michel and New York, NY Company, Inc. PHMB PolyhexamethyleneArch UK Biocides Castleford, UK biguanide, (Cosmocil 100) TBC Tributylcitrate Morflex Inc. Greensboro, NC

Comparative Examples C1-C3 and Examples 1-3

The Examples shown in Table 2 were prepared by first mixing IPA with PVPand Ethocel and heating in an oven at 122° F. (50° C.) and mixing untildissolved. Next Myristyl alcohol was added and heated at 122° F. (50°C.) until dissolved. Separately, FD&C Blue 1 dye was added to water anddissolved. Ester and glycerol were added to the alcohol solution andmixed. The water solution was then added to the alcohol solution, andmixed. Finally, CHG was added and solution, which was then well mixed.The components are in units of grams unless otherwise noted.

TABLE 2 Components Control C1 C2 C3 Ex. 1 Ex. 2 Ex. 3 Ethocel 100 — 0.80.8 0.8 0.8 0.8 0.8 Glycerol — 0.4 0.4 0.4 0.4 0.4 0.4 PVP — 0.2 0.2 0.20.2 0.2 0.2 IPA 64.5 64.5 64.5 64.5 64.5 64.5 64.5 Ester None TEC DBSTEC DBS TEC DBS Ester Amount — 5.0 0.75 0.75 0.75 0.75 0.75 Myristyl OH— — — — 5.0 5.0 2.5 CHG 12.23 12.23 12.23 12.23 12.23 12.23 12.23 Water23.26 16.86 21.11 21.11 16.11 16.11 18.61 FD&C Blue 1 0.01 0.01 0.010.01 0.01 0.01 0.01 Ave. Peel force 141.75 105.95 109.75 147.44 187.52197.12 212.50 (grams/inch) Ave. Peel 55.8 41.7 43.2 58.1 73.8 77.6 83.7force (grams/cm)

Examples 4-8

Examples 4-8 were prepared by first dissolving the fatty alcohol in IPA.After the fatty alcohol was dissolved, water and the remainingcomponents were added followed finally by adding the CHG to obtain thefinal formulations whose compositions are shown in Table 3, below. Theseformulations were tested according to the Direct Inoculation FilterAssay described above.

TABLE 3 Component % w/w Control Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 IPA 70.069.8 69.6 70.0 70.0 69.9 Cetyl alcohol — 4.0 4.0 4.0 4.0 4.0 Ester % —2.0 2.0 2.0 2.0 2.0 Ester type — DBS TBC IPP DIPA DBS Acetone — 5.2 5.15.2 5.0 5.0 CHG 2.0 2.0 2.0 2.0 2.0 2.2 Water 28.0 17.0 17.3 16.8 17.016.9 Total 100.0 100.0 100.0 100.0 100.0 100.0 Log Red. 2.1 1.7 3.6 1.85.1 1.5

All these formulations have pleasant skin feel and dry rapidly to a forma dry, non-tacky layer when applied to skin.

Table 3 above shows the effect of the emollient ester class andstructure on the log reduction of E. faecalis. All formulations showedresidual activity against this bacterial strain. The medium chain lengthesters, tributyl citrate and diisopropyl adipate, significantly enhancedthe bactericidal activity of the CHG in these dried waxy coatings.Longer chain esters such as isopropyl palmitate did not enhance theactivity of the CHG when challenged with E. faecalis. Increasing theconcentration of CHG in the starting formula by 10% did not increase thebactericidal of the formulation but using a medium chain estersignificantly enhanced the bactericidal activity.

Comparative Examples C4 and C5 and Examples 9-19

Examples 9-19 and Comparative Examples C4-C5 were prepared by firstdissolving the fatty alcohol in 200 proof Ethanol (EtOH). After thefatty alcohol was dissolved, water and the remaining components wereadded followed finally by adding CHG to obtain the final formulationswhose compositions are shown in Tables 4 and 5, below. Theseformulations were tested according to the Direct Inoculation FilterAssay described above. The amounts of the components in Tables 4 and 5are in grams unless otherwise noted. The total weight of each preparedExample was 60 grams.

TABLE 4 Components C4 C5 Ex. 9 Ex. 10 Ex. 11 Ex. 12 Ex. 13 Cetyl OH as0.0% 0.0% 3.0% 4.5% 3.0% 6.0% 1.5% % of Total TBC as % of 3.0% 6.0% 6.0%4.5% 3.0% 6.0% 1.5% Total Cetyl OH — — 1.8 2.7 1.8 3.6 0.9 TBC 1.8 3.63.6 2.7 1.8 3.6 0.9 EtOH 45.60 44.16 42.72 42.72 44.16 41.28 45.60 CHG6.30 6.30 6.30 6.30 6.30 6.30 6.30 Water 6.30 5.94 5.58 5.58 5.94 5.226.30 Total Wt. 60.0 60.0 60.0 60.0 60.0 60.0 60.0 Log 5.3 5.3 5.3 4.35.3 4.3 5.5 Reduction

TABLE 5 Ex. Ex. Ex. Ex. Ex. Ex. Control Control Components 14 15 16 1718 19 A B Cetyl OH as 3.0% 0.6% 1.5% 6.0% 4.5% 3.0% 0.0% 0.0% % of TotalTBC as % of 0.0% 3.0% 4.5% 0.0% 1.5% 3.0% 0.0% 0.0% Total Cetyl OH 1.83.6 0.9 3.6 2.7 1.8 — — TBC — 1.8 2.7 — 0.9 1.8 — — EtOH 45.60 42.7244.16 44.16 44.16 44.16 47.04 47.04 CHG 6.30 6.30 6.30 6.30 6.30 6.306.30 6.30 Water 6.30 5.58 5.94 5.94 5.94 5.94 6.66 6.66 Total Wt. 60.060.0 60.0 60.0 60.0 60.0 60.0 60.0 Log 2.8 4.2 5.7 2.5 4.7 5.8 1.9 1.9Reduction

Examples 20-40

Examples 20-40 were prepared by first dissolving the fatty alcohol in200 Proof Ethanol (EtOH). After the fatty alcohol was dissolved, waterand the remaining components were added followed finally by adding CHGto obtain the final Example formulations whose compositions are shown inTables 6-8, below. The amounts of the components in Tables 6, 7 and 8are in grams unless otherwise noted. The total weight of each preparedexample was 60 grams. These formulations were tested according to theDirect Inoculation Filter Assay described above. Log Reduction 2 wasmeasured two weeks after Log Reduction 1.

TABLE 6 Components Ex. 20 Ex. 21 Ex. 22 Ex. 23 Ex. 24 Ex. 25 Ex. 26Fatty Acid 80% 20% 35% 20% 65% 20% 80% Fatty Acid Myristyl MyristylMyristyl Myristyl Myristyl Cetyl Cetyl Type Alcohol Alcohol AlcoholAlcohol Alcohol Alcohol Alcohol Emollient TBC DBA DBS TBC DIPS DIPS DBSType DBA — 2.88 — — — — — DIPA — — — — — — — DBS — — 2.34 — — — 0.72DIPS — — — — 1.26 2.88 — TBC 0.72 — — 2.88 — — — Cetyl OH — — — — — 0.722.88 Myristyl OH 2.88 0.72 1.26 0.72 2.34 — — EtOH 48.00 48.00 48.0048.00 48.00 48.00 48.00 CHG 6.30 6.30 6.30 6.30 6.30 6.30 6.30 Water2.10 2.10 2.10 2.10 2.10 2.10 2.10 Log Red. 1 5.1 3.7 5.2 6.4 3.9 4.21.8 Log Red. 2 6.6 4.8 4.5 5.9 4.7 2.5 1.9

TABLE 7a Components Ex. 27 Ex. 28 Ex. 29 Ex. 30 Ex. 31 Ex. 32 Ex. 33 Ex.34 Fatty Acid 80% 80% 65% 20% 35% 80% 80% 20% Fatty Acid Myristyl CetylCetyl Cetyl Cetyl Cetyl Cetyl Myristyl Type OH OH OH OH OH OH OH OHEmollient DBS DIPS DIPA DIPA TBC DBA DBS DIPA Type DBA — — — — — 0.72 —— DIPA — — 1.26 2.88 — — — 2.88 DBS 0.72 — — — — — 0.72 — DIPS — 0.72 —— — — — — TBC — — — — 2.34 — — — Cetyl OH — 2.88 2.34 0.72 1.26 2.882.88 — Myristyl OH 2.88 — — — — — — 0.72 EtOH 48.00 48.00 48.00 48.0048.00 48.00 48.00 48.00 CHG 6.30 6.30 6.30 6.30 6.30 6.30 6.30 6.30Water 2.10 2.10 2.10 2.10 2.10 2.10 2.10 2.10 Log Red. 1 4.2 3.0 5.7 4.45.9 4.5 3.5 6.4 Log Red. 2 3.4 2.2 5.2 4.5 6.8 4.0 2.3 5.4

Examples 34b and PHMB Control

Examples 34b and PHMB Control were prepared by the same method asExamples 20-40, above, adding PHMB instead of CHG to obtain theformulations shown in Table 7b, below. The amounts of the components inTable 7b are in grams. The total weight of each prepared example was 60grams. These formulations were tested according to the DirectInoculation Filter Assay described above. The results of Table 7b showthat neither the hydrophobic fatty component nor the emollient esteradversely affect the antimicrobial activity of the composition, and inmost cases, improve the antimicrobial efficacy of the antimicrobialcomposition.

TABLE 7b PHMB Components Control Ex. 34b Fatty Acid 20% 20% Fatty AcidType Myristyl Myristyl OH OH Emollient Type DIPA DIPA DIPA — 2.88Myristyl OH — 0.72 EtOH 48.00 48.00 PHMB 1.20 1.20 Water 10.80 10.80 LogReduction 3.1 3.1

TABLE 8 Table 8 Components Ex. 35 Ex. 36 Ex. 37 Ex. 38 Ex. 39 Ex. 40Control Fatty Acid 20% 80% 80% 20% 20% 80% — Fatty Acid MyristylMyristyl Cetyl Cetyl Cetyl Myristyl — Type Alcohol Alcohol AlcoholAlcohol Alcohol Alcohol Emollient DIPA DIPA TBC DBS DBA DBA — Type DBA —— — — 2.88 0.72 — DIPA — 0.72 — — — — — DBS — — — 2.88 — — DIPS 2.88 — —— — — — TBC — — 0.72 — — — — Cetyl OH — — 2.88 0.72 0.72 — — Myristyl OH0.72 2.88 — — — 2.88 — EtOH 48.00 48.00 48.00 48.00 48.00 48.00 48.00CHG 6.30 6.30 6.30 6.30 6.30 6.30 6.30 Water 2.10 2.10 2.10 2.10 2.102.10 5.70 Log Red. 1 4.2 5.9 4.1 3.1 5.3 6.4 3.5 Log Red. 2 3.9 6.2 4.82.0 4.7 6.6 3.0

Comparative Examples C6a-C10a

Comparative Examples C6a-C10a were prepared in a similar manner toExamples 1-3, above. These Examples are shown in Tables 9a, below, withall components listed in units of percent weight/weight (% w/w). Eachformulation was evaluated for skin feel by placing about 0.5 g of theformulation on a forearm and allowing the formulation to dry for about90 seconds followed by evaluation of the treated skin with a cleanfinger. The results are also shown in Tables 9a, below. Overall, thisexample shows the superior skin feel provided by the fatty component andthe emollient ester.

TABLE 9a Components C6a C7a C8a C9a C10a EtOH 80 80 80 80 80 CHG 1.9 1.91.9 1.9 1.9 Glycerin 0.2 0.2 0.2 0.2 0.2 DIPS — 1 2 0.5 1.5 Cetyl OH — —— — — Water 17.9 16.9 15.9 17.4 16.4 Feel Described Slight Slight Oily,Dry Slight stickiness tack slippery tack Acceptable Feel No No No Yes No

Comparative Examples C6b-C10b

Comparative Examples C6b-C10b were prepared by the same method asComparative Examples C6a-C10a, but on a separate occasion. TheseExamples are shown in Tables 9b, below, with all components listed inunits of percent weight/weight (% w/w). These formulations were testedaccording to the Direct Inoculation Filter Assay described above andtheir results are shown in Tables 9b, below.

TABLE 9b Components C6b C7b C8b C9b C10b EtOH 80 80 80 80 80 CHG 1.9 1.91.9 1.9 1.9 Glycerin 0.2 0.2 0.2 0.2 0.2 DIPS — 1 2 0.5 1.5 Cetyl OH — —— — — Water 17.9 16.9 15.9 17.4 16.4 Log 0.8 1.0 0.9 1.3 1.1 Reduction

Examples 41a-45a

Examples 41a-45a were prepared in a similar manner to Examples 1-3,above. These Examples are shown in Tables 10a, below, with allcomponents listed in units of percent weight/weight (% w/w). Eachformulation was evaluated for skin feel by placing about 0.5 g of theformulation on a forearm and allowing the formulation to dry for about90 seconds followed by evaluation of the treated skin with a cleanfinger. The results are also shown in Tables 10a, below. Overall, thisexample shows the superior skin feel provided by the fatty component andthe emollient ester.

TABLE 10a Components Ex. 41a Ex. 42a Ex. 43a Ex. 44a Ex. 45a EtOH 80 8080 80 80 CHG 1.9 1.9 1.9 1.9 1.9 Glycerin 0.2 0.2 0.2 0.2 0.2 DIPS — 1 21.5 0.5 Cetyl OH 3 3 3 3 3 Water 14.9 13.9 12.9 13.4 14.6 Feel Veryslight tack, Dry feel Dry feel, Dry feel Dry feel Described gone in 2min silky Acceptable Yes Yes Yes Yes Yes Feel

The results in the Table 10a, above, indicate that both the cetylalcohol and diisopropyl sebacate reduce the stickiness of the CHGformulation. When diisopropyl sebacate (DIPS) is used alone, atconcentrations of 1% diisopropyl sebacate or higher, undesirable tack isobserved. At 2% diisopropyl sebacate, a highly undesirable oily filmforms on the skin. However, by incorporating 3% cetyl alcohol (a waxyfatty alcohol), the formulations containing 1% diisopropyl sebacate orhigher are not tacky and have a light, dry feel. This example shows thatformulations containing both an emollient ester and fatty alcohol haveimproved feel even when higher levels of emollient esters such asdiisopropyl sebacate are used.

Examples 41b-45b

Examples 41b-45b were prepared by the same method as Examples 41a-45a,above, but on a separate occasion. These Examples are shown in Tables10b, below, with all components listed in units of percent weight/weight(% w/w). These formulations were tested according to the DirectInoculation Filter Assay described above and their results are shown inTables 10b, below.

TABLE 10b Components Ex. 41b Ex. 42b Ex. 43b Ex. 44b Ex. 45b EtOH 80 8080 80 80 CHG 1.9 1.9 1.9 1.9 1.9 Glycerin 0.2 0.2 0.2 0.2 0.2 DIPS — 1 21.5 0.5 Cetyl OH 3 3 3 3 3 Water 14.9 13.9 12.9 13.4 14.6 Log 1.9 2.51.0 1.4 2.6 Reduction

Example formulations C10a and Ex. 44a were further tested in anotherskin feel test. The difference between the two formulas is that Ex. 44acontains 3.0% w/w cetyl alcohol. Prior to testing for skin feel, handswere washed with bar soap and thoroughly rinsed with water and allowedto dry. An amount of 0.8 g of each formulation was added to the palm ofone hand and then the two hands were rubbed together for 30 seconds,followed by a 30 second dry time. After the dry time, the skin surfacefeel was noted. The results are summarized in Table 11, below. This testsimulates a single use application in a health care facility.

TABLE 11 Drying to Example skin Feel Description C10a No Hands feeltacky and grabby when rubbed together. Hands cannot be rubbed togetherdue to excessive friction at the surface. Ex. 44a No Hands feel smoothand dry. Overall feel is good.

Comparative Example C10 and Ex. 44 both contained 80% w/w ethanol andwere not drying to the skin. However Ex. 44, containing both 1.5% w/wemollient ester and 3.0% w/w fatty alcohol had superior cosmetic skinfeel.

Examples 46a-48a

Examples 46a-48a were prepared by first combining the ethanol phaseingredients (ethanol, tributyl citrate, and waxes) and then stirred toform a clear solution. Deionized water was then added and stirredfollowed by the CHG. The final formulations were stirred for 2 minutesto ensure thorough mixing. These Examples are shown in Table 12a, below,and all components are in units of grams. Examples 46-48 all have goodskin feel and dried rapidly on after application to the skin to form asmooth layer with no tack or greasy feel.

TABLE 12a Components Example 46a Example 47a Example 48a EtOH 36.7134.49 39.24 Myristyl lactate 1.91 — — GML — 1.66 — Dodecyl glycerylether — — 0.50 Cetyl OH — — 1.07 TBC 1.04 1.45 1.50 CHG (grams 20%soln.) 5.12 6.26 5.03 Water 5.13 6.11 2.76

Examples 47b-48b

Examples 47b and 48b were prepared by the same method as Examples46a-48a, above, but on a separate occasion. These Examples are shown inTable 12b, below, and all components are in units of grams. Theseformulations were tested according to the Direct Inoculation FilterAssay described above and their results are shown in Tables 12b, below.

TABLE 12b Components Example 47b Example 48b EtOH 34.49 39.24 GML 1.66 —Dodecyl glyceryl ether — 0.50 Cetyl OH — 1.07 TBC 1.45 1.50 CHG (grams20% soln.) 6.26 5.03 Water 6.11 2.76 Log Reduction 5.4 5.4

Examples 49-53

Examples 49-53 were made by first preparing a polymer premix of Ethocel,Glycerol, PVP and IPA. The remaining components were then added andstirred, with water and CHG added last. The final formulations werestirred for 2 minutes to ensure thorough mixing. The prepared Exampleswere evaluated according to the Skin Panel Evaluation proceduredescribed above. The components and results for Examples 49-53 and acontrol are presented in Table 13, below.

Bacterial counts were converted to log₁₀ CFU/cm² before analysis. Countsof less than 1 CFU/cm² were treated as 1 CFU/cm² such that the logtransformation was zero. Log reductions were calculated by subtractingthe post treatment log count from the baseline log count from the samearea of the back. The baseline CFU counts averaged 3.1 logs.

TABLE 13 Components Ex. 49 Ex. 50 Ex. 51 Ex. 52 Ex. 53 Control Ethocel100 1.12 1.12 1.12 1.12 1.12 — Glycerol 0.56 0.56 0.56 0.56 0.56 — PVP0.28 0.28 0.28 0.28 0.28 — IPA 90.3 90.3 90.3 90.3 90.3 90.3 Acetone — —— — 14 — Myristyl OH 3.5 4.2 2.8 3.15 3.5 — TEC — — — — — — ATEC — — — —0.35 — ATBC — 4.2 — 6.3 0.35 — TBC — — — — 2.8 — DBS 5.32 — — — — —Permethyl 97A — — 2.8 — 3.5 — Permethyl 99A — — — 2.1 — — GDL — — — — —— Water 21.77 22.19 24.99 19.04 7.59 32.55 FD&C Blue 1 0.035 0.035 0.0350.035 0.035 0.035 CHG 17.12 17.12 17.12 17.12 17.12 17.12 Total wt.grams 140 140 140 140 141.5 140 Log Red 2.3 2.1 1.9 2.1 2.3 1.5

Various modifications and alterations of the present invention will beapparent to those skilled in the art without departing from the scopeand spirit of the present invention. The Examples described in thisapplication are illustrative of the possibilities of varying the type,quantity and ratio of composition as well as the methods for makingformulations of the present invention. The complete disclosures of allpatents, patent applications, and publications recited herein areincorporated by reference, as if individually incorporated by reference.

1. An antimicrobial composition comprising: a) a C₂-C₅ lower alcoholpresent in an amount of at least 35 wt-%; b) a fatty componentcontaining one or more free hydroxyl groups selected from the groupconsisting of C₁₂-C₂₁ fatty alcohols, C₁₂-C₂₁ fatty ethers, C₁₂-C₂₁fatty amides, and combinations of all of the foregoing; wherein thefatty component is present in the composition in an amount of at least 2wt-%; and c) a cationic antimicrobial agent; wherein the antimicrobialcomposition is free of surfactants with an HLB greater than 6; andwherein the antimicrobial composition is essentially free of hydrophilicpolymers.
 2. An antimicrobial composition comprising: a) a C₂-C₅ loweralcohol present in an amount of at least 35 wt-%; b) a fatty componentcontaining one or more free hydroxyl groups selected from the groupconsisting of C₁₂-C₂₁ fatty alcohols, C₁₂-C₂₁ fatty esters, C₁₂-C₂₁fatty ethers, C₁₂-C₂₁ fatty amides, and combinations of all of theforegoing; c) a cationic antimicrobial agent; and (d) an emollient esterselected from the group consisting of diesters of bibasic acids,triesters of citric acid, diesters of diols, triesters of triols, andcombinations thereof, wherein the emollient ester is present in anamount greater than 1 wt-% based on the total weight of the composition.3-8. (canceled)
 9. The antimicrobial composition of claim 1, furthercomprising water, wherein the lower alcohol to water weight ratio isbetween 40:60 to 95:5.
 10. The antimicrobial composition of claim 1,wherein the ratio of the fatty component to the cationic antimicrobialagent is at least 0.5:1.
 11. (canceled)
 12. The antimicrobialcomposition of claim 2, wherein the ratio of the combination of thefatty component and the emollient ester to the cationic antimicrobialagent is at least 1:1.
 13. (canceled)
 14. The antimicrobial compositionof claim 2, wherein the fatty component is present in the composition inan amount of at least 2 wt-% based on the total weight of theantimicrobial composition.
 15. The antimicrobial composition of claims2, wherein the emollient ester is present in the composition in anamount of at least 2 wt-% based on the total weight of the antimicrobialcomposition.
 16. The composition of claim 1, further comprising anemollient ester selected from the group consisting of diesters ofbibasic acids, triesters of citric acid, diesters of diols, triesters oftriols, and combinations thereof.
 17. The antimicrobial composition ofclaim 1, wherein the C₁₂-C₂₁ fatty alcohol is selected from the groupconsisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearylalcohol, isocetyl alcohol, octyl dodecanol, 2 hexyl decanol, 2 hexyldodecanol, and combinations thereof. 18-19. (canceled)
 20. Theantimicrobial composition of claim 2, wherein the emollient ester has asolubility in water of less than 2 wt-%.
 21. The antimicrobialcomposition of claim 20, wherein the emollient ester is a liquid at roomtemperature. 22-25. (canceled)
 26. The antimicrobial composition ofclaim 2, wherein at least one of the fatty component and the emollientester has a melt temperature greater than 23° C. 27-33. (canceled) 34.The antimicrobial composition of claim 1, wherein the cationicantimicrobial agent is selected from the group consisting ofchlorhexidine, chlorhexidine digluconate, chlorhexidine diacetate,chlorhexidine dimethosulfate, and chlorhexidine dilactate salts,polyhexamethylenebiguanide, benzalkonium halides, and combinationsthereof.
 35. (canceled)
 36. The antimicrobial composition of claim 2,wherein the emollient ester is selected from the group consisting ofdibutyl adipate, diisopropyl adipate, diisobutyl adipate, dihexyladipate, diisopropyl sebacate, dibutyl sebacate, tributyl citrate,diesters of butanediol and hexanediol, propylene glycol dicaprylate, andcombinations thereof. 37-39. (canceled)
 40. A method of improving thewet adhesion of medical adhesive article, comprising applying acomposition comprising: a) a C₂-C₅ lower alcohol present in an amount ofat least 35 wt-%; b) a fatty component containing one or more freehydroxyl groups selected from the group consisting of C₁₂-C₂₁ fattyalcohols, C₁₂-C₂₁ fatty esters, C₁₂-C₂₁ fatty ethers, C₁₂-C₂₁ fattyamides, and combinations of all of the foregoing; c) a cationicantimicrobial agent; and applying a medical adhesive article over thecomposition; wherein the medical adhesive article has improved adhesionto skin as measured by the Wet Skin Adhesion test. 41-43. (canceled) 44.The antimicrobial composition of claim 2 wherein the ratio of the fattycomponent to the cationic antimicrobial agent is at least 0.5:1.
 45. Theantimicrobial composition of claim 2, wherein the C₁₂-C₂₁ fatty alcoholis selected from the group consisting of lauryl alcohol, myristylalcohol, cetyl alcohol, stearyl alcohol, isocetyl alcohol, octyldodecanol, 2 hexyl decanol, 2 hexyl dodecanol, and combinations thereof.46. The antimicrobial composition of claim 16, wherein the emollientester has a solubility in water of less than 2 wt-%.
 47. Theantimicrobial composition of claim 2, wherein the cationic antimicrobialagent is selected from the group consisting of chlorhexidine,chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidinedimethosulfate, and chlorhexidine dilactate salts,polyhexamethylenebiguanide, benzalkonium halides, and combinationsthereof.
 48. The antimicrobial composition of claim 16, wherein theemollient ester is selected from the group consisting of dibutyladipate, diisopropyl adipate, diisobutyl adipate, dihexyl adipate,diisopropyl sebacate, dibutyl sebacate, tributyl citrate, diesters ofbutanediol and hexanediol, propylene glycol dicaprylate, andcombinations thereof.